Chemica Pollutants and Itching: What Does Nerve Growth Factor Have to Do With It?

Background: Nerve growth factor (NGF) is a neurotropin that is important for the growth and survival of neurons and is believed to be important to preventing neural degeneration (in some cases and not others) and is present in larger amounts in inflamed tissue. (Wipedia, Pehar) On the other hand, it upregulates nociceptors and may play a role in neuropathic pain.  Altered nociception and ASICs signaling have both been implicated as a factors in multiple chemical sensitivity (Pall) and other environmentally-induced health conditions. In certain studies it has also been shown that the level of NGF is correlated to the severity of itching in atopy. Toluene is an air pollutant and is found in low or high amounts in homes and commercial buildings.

Two studies may shed more light on understanding the "itch" that is commonly associated with some cases of environmental illness. The first study provides an explanation of how air pollutants, in this case, toluene effects physiological systems. According to the first study findings, low-level toluene induced a significant increase in CCL2 (MCP-1) and CCL3 and cells positive for nerve growth factor while showing insignificant markers for oxidative stress and HO-1 in controls and immunized mice. Immunized mice were treated to model allergic animals. The findings of this study show that volatile organic compounds (ie toluene) enhance nerve growth factor production and airway inflammation is more severe in allergic animals.(Fujiama) Interestingly, another study, shows that dioxin, an activator of the AhR, caused itching when the experiment animal was exposed to another generally inocuous stimulus. In the study, it was demonstrated that the itching of this type was alleviated with pharmaceuticals that reduce skin levels of NGF. (Ono)

HEIRS Library Tags: nerve growth factor

Notes:

• There is an important relationship of Nrf2 and HO-1 in the consequences of activity by nerve growth factor which may include reduction of ROS and protection against endogenous environmental insults including dopamine toxicity. (Salinas)

Fujimaki, H., Tin-Tin-Win-Shwe, Yamamoto, S., Nakajima, D., and Goto, S. (2009). The expression of nerve growth factor in mice lung following low-level toluene exposure. Toxicology letters, 191(2-3):240-245. http://www.citeulike.org/user/HEIRS/article/5808711#
Pall, M. L. and Anderson, J. H. (2004). The vanilloid receptor as a putative target of diverse chemicals in multiple chemical sensitivity. Archives of environmental health, 59(7):363-375. http://www.citeulike.org/user/HEIRS/article/5911051
Diogenes, A., Akopian, A. N., and Hargreaves, K. M. (2007). Ngf up-regulates trpa1: Implications for orofacial pain. J Dent Res, 86(6):550-555. http://www.citeulike.org/user/HEIRS/article/3682087
Yamaguchi, J., Aihara, M., Kobayashi, Y., Kambara, T., and Ikezawa, Z. (2009). Quantitative analysis of nerve growth factor (ngf) in the atopic dermatitis and psoriasis horny layer and effect of treatment on ngf in atopic dermatitis. Journal of dermatological science, 53(1):48-54. http://www.citeulike.org/user/HEIRS/article/6453209
Ono, R., Kagawa, Y., Takahashi, Y., Akagi, M., and Kamei, C. (2009). Effect of 2,3,7,8- tetrachlorodibenzo-p-dioxin on scratching behavior in mice. International immunopharmacology. http://www.citeulike.org/user/HEIRS/article/6409196
Pehar, M., Vargas, M. R., Robinson, K. M., Cassina, P., Diaz-Amarilla, P. J., Hagen, T. M., Radi, R., Barbeito, L., and Beckman, J. S. (2007). Mitochondrial superoxide production and nuclear factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced motor neuron apoptosis. J. Neurosci., 27(29):7777-7785. http://www.citeulike.org/user/HEIRS/article/3733200?updated=1262024743
Salinas, M., Diaz, R., Abraham, N. G., Ruiz de Galarreta, C. M., and Cuadrado, A. (2003). Nerve growth factor protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a phosphatidylinositol 3-kinase-dependent manner. Journal of Biological Chemistry, 278(16):13898-13904. http://www.citeulike.org/user/HEIRS/article/6456500

TLR as Inflammatory Mediators: Why Ozone and MCS Do Not Mix

Several recent observations have revealed possible routes of physiological consequences of toxicant exposure (ie ozone) that may be related to symptoms of MCS. It has been suggested activation of TRP channels may play an important role causal in MCS. (Pall) Bessac and Jordt write, "that both the TRPA1 and TRPV1 receptor may contribute to chemical hypersensitivity, chronic cough, and airway inflammation in asthma, COPD, and reactive airway dysfunction syndrome" and other reports link TRPA1 to asthma.(Drug Disovery) Activations of these receptors will increase their expression, therefore, increasing the likelihood of activation (and symptoms) by exposures that activate them. Or on the other hand, Bessac writes, cross-desensitization exists by one chemical may desensitize it to another. As we noted over a year ago, changes in these receptors can occur by interactions with other proteins including IGF-1 and inflammatory cytokines that may alter these receptors functioning which may cause "aberrant signaling".

Recently it has been demonstrated that ozone activates TRPA1 channels and TRPA1 channels have been shown to be upregulated by the inflammatory cytokine MCP-1/ pathway which has been discussed at length in other blogs. Ozone and smoking promote a process called oxidation of phospholipids (oxPL) that generates ROS from NADPH oxidase activation, increase MCP-1, negatively regulate Nrf2 and are associated with autoimmune diseases such as lupus, RA and Parkinson's disease. OxPL are generated during inflammatory conditions and inhibit the full differention of dendritic cells and therefore restrict normal adaptive immune response. (Bluml) Recently other research has provided evidence that additional ozone reactions can be caused from abnormal enzymatic actions of glutathione which, by he way, is also regulated by Nrf2 through other proteins. In addition, ozone contributes to airway hypersensitivity and hyperresponsiveness through the modulation of TLR receptors and other green house gases may play a part in the "learned response" tied possibly to physiological response in MCS, may  potentiate the effects of lead-based paint and increase related health risks and cause panic-like behavior.

Just in case you have heard that ozone generators are physiologically calming...well, according to the research, quite the opposite seems to be true. For instance, as new study shows there is a sensor in the brain for CO2, another greenhouse gas, that will cause panic-attacks. Such behaviors are crucial for animals for survival to be able to "sense" and prevent biological suffocation and "aberrant signaling" of TLR receptor may decrease the threshold of activation of these sensors. Keely explains that "epithelial hypoxia" in the gut results in a 40-fold increase in translocation of gram-negative bacteria, regardless of intestinal barriar function. In the gut, hypoxia is associated with acute and chronic inflammation (ie IBD) and its presence initiates factors that exploits the intestinal environment to achieve the translocation process. One can assume that similar sensory processes that activate panic or flight response may be present in other tissues including the lungs and gut. Additionally, it has been demonstrated that viruses activate TLR receptors but the mechanism is slightly different.

TLR4 receptors recognize LPS endotoxin which is the a component of the wall of gram-negative bacteria. Several reports now suggest that a route of CFS is endotoxin exposure.Endotoxin is the result of lysis of bacteria from immune cells and therefore, will be present whereever there is inflammation. Of course, minimizing exposures that contain bacteria is one way to reduce TLR signaling. There are other TLR receptors that also initiate immune responses to other contaminants.   Recent evidence has demonstrated that saturated fat "angers" the immune system by interacting with TLR4 but the exact process of how saturated fat does this is unclear. Cani has noted that LPS in high-fat diets is 2 to 3 times greater and that LPS-containing  proportion is greater in the high-fat diet gut.  Other conditions may favor altered TLR4 signaling and because they initiate a variety of events inside the cell, the absence or dysregulation of the antioxidant system can lead to an exacerbation of inflammatory events because it modulates cytokines production such as pro-inflammatory Il-1 and Tnf-a and the anti-inflammatory cytokine Il-10 which modulates sickness syndrome. The antioxidant system Nrf2 supports other proteins in mitochondrial biogenesis which it has been reported that exposure to chemicals has an effect on cellular respiration and alters mitochondrial function.  Altered TLR signaling also may contribute to neuropathic pain. Other effects include alteration in neurotransmission such as dopamine which may contribute to Parkinson's disease and other neurodegenerative diseases.

I have written several essays on TLR receptors and how they interact with the immmune system from different environmental toxicants which can be read here. Also, to read citations for this article click here.

MCP-1 is associated with Type 2 diabetes and CVD mortality

Monocyte chemoattractant protein-1 (MCP-1) is increased in individuals with Type 2 diabetes and is associated with long-term cardiovascular disease (CVD) mortality, report researchers

.

Link

Why Endotoxin Can Increase Pain,Chemical and Mold Sensitivity and Causes Sickness Behavior!

Toll-like receptors: are a class of proteins that play a key role in the innate immune system. (Wipedia)

Background: Binding to toll-like receptors may initiate inflammatory responses including the production of chemokines. They mainly signal through NF-kappaB and increase transcription of inflammatory proteins Il-1b, Tnf-a, CCL2 (MCP-1) etc. (Devaraj) These are receptors that are highly expressed and are considered to be a link between diet and metabolism and are implicated as important factors in a number of health conditions including lupus, atherosclerosis and diabetes. (Dasu) We have noted in other blogs that they may play an important role in conditions that are most often considered "environmental illnesses" including chronic fatigue syndrome and/or contribute to symptoms of chemical sensitivity. To put it simply, toll-like receptors are considered signal transducers that initiate inflammatory processes and two common ligands are LPS endotoxin (which has been implicated in CFS) and saturated fatty acids. The ligands that bind TLR contain a "molecular pattern" the TLR recognizes and may be present in microbial and non-microbial agents or may be responsive to signals generated at the site of inflammation or from endogenously-produced proteins like heat shock proteins. Thus, their activites become a concern when ever pathogenic exposure or inflammation may be present.

The distribution of the toll-like receptors is different in different tissues but include epithelia and endothelia in the intestinal tract, the respiratory tract, the blood-brain barrier, etc. It is now believed that there is a commensal relationship that exists between the gut microbiota and TLR to maintain gut integrity (Hopkins) and may involve epigenetic influences and down-regulation of TLR gene transcription. (Takahashi)    It has been determined that TLR2 and TLR4 bind to gram positive and negative bacteria respectively. However, the production of one type of TL receptor may induce the induction of the other. Devaraj demonstrated that type-1 diabetes and increased levels of IL-1b and TNF-a is correlated with expression of TLR and also endotoxin "contribute to the inflammatory burden by activating TLR receptors" and suggests their instrumental in diabetes pathology. In addition, it has also been determined that high glucose levels can stimulate the expression of these receptors in monocytes. While toll-like cells are involved in cytokine production and cell activation, the inflammatory responses initiated by activation of receptors may last long after the initial stimulus is gone or may potentiate the inflammatory responses of other insults. It may seem beneficial to blunt the responses of TLR, but it may be more harmful by making the organism more susceptible to infection.(Hopkins) On the other hand, aberrant signaling from TLR can lead to autoimmune-type conditions as we noted above.

Other studies demonstrate that the expression of TLR are widespread are can activate microglia and astocytes and play a role in neuroinflammatory responses. Microglia are sensory-type cells that are the main source of inflammatory mediators in the nervous system.  Some studies show that TLR activation of microglia leads to an increase in NO, superoxide and other cytokines and that TLR-deficient microglia demonstrated a significant reduction in several types of inflammatory responses. Obata confirmed TLR3 has an important role in the development of tactile allodynia after nerve injury and blocking these receptors may provide effective treatment for neuropathic pain which has been linked to fibromyalgia. Recent findings are suggestive of the notion that fibromyalgia is a "disorder of central processing with neuroregulation/
transmission dysfunction" (NFA) and TLR4 may initiate an inflammatory profile through NF-kappaB at least in a subset of fibromyalgia patients. In one model of neuropathic pain, tactile allodynia was "abrogated" in CCR2 mice which is the receptor for CCL2 (MCP-1), the inflammatory cytokines activated by NF-kappaB and has been suggested as a possible marker for fibromyalgia. It also plays a very important role in the development of neuroinflammation via the TNF-a/CCL2/CCR2 pathway. From this, it has been suggested that activation of immune cells and microglia peripherally and in neurons may contribute to inflammatory and neuropathic pain states and (Abbadie) importantly, it is now understood that TLR agonists modulates CCR2 expression and CCL2 responsiveness. (Souto, Parker) Jo et al explains peripheral injuries that lead to neuropathic states causes pathology not only in the damaged nerves but also causes changes in the central processing of sensory information and glial activation may facilitate "noxious signal transduction" even after the initial injury has healed. Therefore, TLR may not only initiate neuropathic pain but also maintain it.  Experts believe nociceptive behavior may influence symptoms of MCS (Pall) and it has been demonstrated pain caused by bacterial infection may be generated through activation of nociceptors via the TLR in neurons. (Wabachi) In addition, TLR responses play a role in viral and parasitic infections, multiple sclerosis, exacerbate injury in ischemia (Kielian) and chronic activation of TLR is associated with anxiety, avoidance and sickness behavior (Hudson) and increased sensitivity to other toxicants (Pestka).

Other reports show in epithelial cells, TLR mediate immune cells production from exposure to particulate matter and contribute to airway hypersensitivity from exposure to ozone. (Williams) More recently, it has been shown that the aryl hydrocarbon receptor (AhR), which plays a role in the detoxification of polyaromatic hydrocarbons and halogenated hydrocarbons, negatively regulates TLR signaling. Animals that are deficient in the AhR exhibit exaggerated inflammatory responses including significant elevations in TNF-a and IL-6 and are highly susceptible to septic shock. (Ogawa, Kimura) We have expressed the belief that the abnormal functioning of the AhR may contribute to environmental illnesses including multiple chemical sensitivity because of its role in detoxification and its relationship to the antioxidant system regulator Nrf2. The Nrf2 protects neurons and other cells against oxidative and environmental insults in primary and secondary injury. TLR activates NF-kappaB through the universale adaptor protein MyD88 and it has been shown that Nrf2 has a "global influence" on MyD88-dependant and independant signaling. Deficiency of Nrf2 dysregulated expression of genes that encode molecular components of innate immunity (e.g., peptidoglycan-recognition proteins, proinflammatory cytokines, chemokines, and adhesion molecules and receptors." (Thimmulappa)

Study Highlight: Pestka provides evidence that the preexposure of a TLR agonist such as LPS endotoxin increases the inflammatory response of DON, a mycotoxin. This response which included production of IL-1b, Il-6, and TNF-a was at levels higher than either produced alone. During the study, preexposure to other TLR agonists, also increased the pro-inflammatory responses of DON in a similar manner as LPS. In addition, similar heightened responses occured from LPS preexposure of TLR and subsequent effects of microbial and non-microbial "agents" including satratoxin, Shiga toxin, zearalenone and toxicants such as nickel chloride, triphenyltin, dinitrochlorobenzene (a known irritant) and dioxin. It has been concluded from this study that prior exposure to TLR agonists (ie endotoxin, saturated fat and others) "might render macrophages highly sensitive to subsequent induction of proinflammatory gene expression by xenobiotics with diverse mechanisms of action." (Pestka)

Notes:

• An important source of bacterial and endotoxin contamination is from our drinking water. Find out more about the importance of healthy water with a clip from the Dr. Oz Show. Other main sources include from the air we breath.
• IRAK-1 is necessary for LPS-mediated suppression of PPARalpha and PGC-1alpha, nuclear factors essential for the expression of anti-oxidative enzymes such as GPX3 and catalase (Maitra) "ROS trafficking(NADPH oxidase) mediates LPS/TLR signals in neutraphils and downstream targets including IRAK-1. Deficiency of Nrf2 predisposes neutraphils to greater responsiveness to LPS which is mediated by increased ROS generation. (Thimmulappa)

Reference Resource:

• Toll-like receptor (TLR)-mediated biology (Hopkins)
  

Follow us: Twitter at HEIRS_EI
Website: HEIRS Health & Home
My Bio: HEIRS Health & Home
Google Group: Environmental Illness: Research to Recovery
HEIRS Environmental Illness Community                 
                 
            
Original document and citations can be accessed here.

Relation of inflammatory chemokines to insulin resistance and hypoadiponectinemia in coronary artery disease patients.

Relation of inflammatory chemokines to insulin resistance and hypoadiponectinemia in coronary artery disease patients.

View Citation in Library

Experimental endotoxemia induces adipose inflammation and insulin resistance in humans

Title: Experimental endotoxemia induces adipose inflammation and insulin resistance in humans.

Summary: "acute inflammation induces systemic IR following modulation of specific adipose inflammatory and insulin signaling pathways."

Mehta, N. N., McGillicuddy, F. C., Anderson, P. D., Hinkle, C. C., Shah, R., Pruscino, L., Tabita-Martinez, J., Sellers, K. F., Rickels, M. R., and Reilly, M. P. (2009). Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes. http://www.citeulike.org/user/HEIRS/article/5908018

Adipose tissue may play role in COPD-related systemic inflammation

Adipose tissue may play role in COPD-related systemic inflammation

Related Posts:
MCP-1 predicts COPD in heavy smokers
Ethnicity influences genetic susceptibility in COPD

Role of MCP-1 in tumor necrosis factor-{alpha}-induced endothelial dysfunction in type 2 diabetic mice

Yang, J., Park, Y., Zhang, H., Gao, X., Wilson, E., Zimmer, W., Abbott, L., and Zhang, C. (2009). Role of mcp-1 in tumor necrosis factor-alpha-induced endothelial dysfunction in type 2 diabetic mice. Am J Physiol Heart Circ Physiol, 297(4):H1208-1216. http://www.citeulike.org/group/6182/article/5843185

MCP-1 predicts COPD in heavy smokers

MCP-1 predicts COPD in heavy smokers

Chronic Fatigue, Insulin Resistance, Il-10 and Sickness Syndrome

Definition:

• Bioaccumulation: refers to the accumulation of substances, such as pesticides, or other organic chemicals in an organism. (Wipedia)

Background: Several months ago we discussed an article the describes the results of a study that revealed a link between accumulation of chemicals and diabetes. That study also noted the relationship was correlated to a higher incidence of obesity. In addition, we have recently described that Nrf2 plays a homeostatic role in adipocytes it now appears Nrf2 plays a modulatory role in adipogenesis and when the Nrf2 activity is impaired there is a greater risk for obesity. We have also discussed at length that chemicals bioaccumulate in fat tissue where they produce inflammatory mediators and decrease regulatory and anti-inflammatory proteins such as PPAR-gamma (which when overregulated can contribute to obesity) and adiponectin and it is assumed now this is also true because high-fat diets may impair Nrf2 which influences the control of inflammatory responses mediators such as Tnf-a and MCP-1/CCL2/CCR2, may prevent or delay activation of the antioxidant system. Nrf2 also is responsible for gene expression for proteins important for mitochondrial respiration such as NRF1 and PPAR-a. The latter being a regulatory factor that cooperates with PGC-1a during mitochondrial biogenesis. Insulin resistance also impairs mitochondrial function and is quite a common characteristic that leads to diabetes and obesity.

Other important things we have noted recently are:

• 
  Sickness syndrome includes a number of behavioral symptoms including fatigue, malaise, increased sensitivity to pain, loss of appetite, anxiety, depression and numerous other symptoms. A recent study has demonstrated that the severity of sickness syndrome depends on the presence or absence of IL-10. If it is present the shorter and less severe the symptoms and if it is absent the patient will experience more severe pathology. In addition, we also noted that MCP-1 is activated by Tnf-a and IL-6 in peripheral tissue to caused neurotransmission in the brain that can incite the inflammatory cascade.
• We also noted that Il-10 is regulated by HO-1 which also is regulated by Nrf2. If the Nrf2 pathway is impaired or inhibited in adipocytes, there is greater opportunity for an elevated inflammatory response in those tissues and the body would have a reduced ability to detoxify an "bioaccumulating" agent that it might be exposed to such as pesticides and other environmental contaminants.
• We have also noted the Nrf2 system can be impaired by exposures to metals, aging factors, other genetic factors, hyperglycemia which is now considered a consequence of environmental or endogenous exposures (H2S).
• 
  
  The Nrf2 regulates and is regulated by the aryl hydrocarbon that mediates the detoxification of PAHs and HAHS including dioxin and ingredients in agricultural products. The toxicity of dioxin is mediated through the AhR and is abnormal function may have an extremely important role in toxicity of endotoxin which Maes describes as a pathway to the development of CFS.

A new study has revealed more important details about Il-10 that sheds more light on the symptoms associated with sickness behavior and chronic fatigue syndrome. This new study demonstrates that Il-10 is important for maintaining insulin sensitivity by protecting muscles from obesity-associated macrophage infiltration of inflammatory cytokines and diet-induced inflammatory responses. In the study, it was shown these cytokines include Tnf-a, Il-6, and CCR2. These are markers important in findings related to CFS and fibromyalgia and other environmental illnesses and develop (You can read about MCP-1 here) as part of the stress response from toxicant insults. This study indicates not only that IL-10 may be used as therapy for diabetes but one can suggest future therapies may also target environment illnesses that have presentations of fatigue, muscular pain and sensitivity. A past study demonstrated that Il-10 prevented alterations in Il-6 hepatic insulin action, signaling, and also Il-6 and lipid-induced insulin signaling in skeletal muscle and therefore support the findings from the study noted above. (Kim) Both studies provides evidence of an important role of Nrf2 in regulating metabolic homeostasis by regulating HO-1/IL-10 and demonstrates how its impairment or inhibition can lead to environmental illness.

HEIRS Environmental Illness Research Blog: Sickness Syndrome, CFS, Fibromyalgia, IL-10 and HO-1

HEIRS Environmental Illness Research Blog: Sickness Syndrome, CFS, Fibromyalgia, IL-10 and HO-1

Activation of MCP-1/CCl2/CCR2 by TNF-a to cause microglial neuroinflammation and alterations in neurotransmission require the presence of the TNFR1. (D' Mello) The Nrf2 pathway has been shown to modulate inflammatory mediators including Tnf-a and the glutamate antiporter system. (Lewerenz) The TNFR1 receptor is important for preconditioning in ischemia to reduce injury from subsequent ischemia through interaction with the EAAT3. The EAAT3 transporter regulates glutamate and also is involved with glutathione synthesis and is present in cortical and striatal neurons. (Suchak) It works cooperatively with xCT to prevent depletion of glutathione caused by high glutamate levels and may be useful in eventual therapy for Parkinson's. (Lewerenz)

D'Mello, C., Le, T., and Swain, M. G. (2009). Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J. Neurosci., 29(7):2089-2102. http://www.citeulike.org/user/HEIRS/article/4079736
Suchak, S. K., Baloyianni, N. V., Perkinton, M. S., Williams, R. J., Meldrum, B. S., and Rattray, M. (2003). The 'glial' glutamate transporter, eaat2 (glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings. Journal of neurochemistry, 84(3):522-532. Suchak, S. K., Baloyianni, N. V., Perkinton, M. S., Williams, R. J., Meldrum, B. S., and Rattray, M. (2003). The 'glial' glutamate transporter, eaat2 (glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings. Journal of neurochemistry, 84(3):522-532. http://www.citeulike.org/user/HEIRS/article/5699931
Pradillo, J., Hurtado, O., Romera, C., Cardenas, A., Fernandeztome, P., Alonsoescolano, D., Lorenzo, P., Moro, M., and Lizasoain, I. (2006). Tnfr1 mediates increased neuronal membrane eaat3 expression after in vivo cerebral ischemic preconditioning. Neuroscience, 138(4):1171-1178. http://www.citeulike.org/user/HEIRS/article/5699676
Lewerenz, J., Klein, M., and Methner, A. (2006). Cooperative action of glutamate transporters and cystine/glutamate antiporter system xc- protects from oxidative glutamate toxicity. Journal of neurochemistry, 98(3):916-925. http://www.citeulike.org/user/HEIRS/article/762845
Lewerenz, J., Albrecht, P., Tien, M.-L. T. L., Henke, N., Karumbayaram, S., Kornblum, H. I., Wiedau-Pazos, M., Schubert, D., Maher, P., and Methner, A. (2009). Induction of nrf2 and xct are involved in the action of the neuroprotective antibiotic ceftriaxone in vitro. Journal of neurochemistry. http://www.citeulike.org/user/HEIRS/article/5627214
Maher, P., Lewerenz, J., Lozano, C., and Torres, J. L. L. (2008). A novel approach to enhancing cellular glutathione levels. Journal of neurochemistry, 107(3):690-700.
http://www.citeulike.org/user/HEIRS/article/3401858

Fibromyalgia, Endoplasmic Reticulum Stress, Neurotoxicity and CAMKII

Many experts now believe pain sensitivity in fibromyalgia is in part, neuropathic pain. "Martinez-Lavin notes that neuropathic pain is stimuli-independent and is accompanied by allodynia and paresthesia, which are also common features of fibromyalgia. He also points out that the most important characteristic of neuropathic pain is not the nerve lesion, but the resulting nerve dysfunction." (Kelly) Nociceptors (ie. TRPV1) can be upregulated in neuropathic conditions in addition to other inflammatory pain disorders. Also, a number of different agents activate nociceptors including those in food, fragrances and chemicals and other noxious stimuli like heat, cold and pH. Hormonals and neurochemical signals such as IGF and H2O2 and cytokines such as MCP-1 can increase the sensitivity of nociceptors which reduce their threshold for activation.
Upon activation of TRP channels, there is a flood of calcium inside the cell. Consistent and long-term activation and subsequent intracellular exposure to increased calcium may result in endoplasmic reticulum stress. Two consequences occur from ER stress 1) the activation of Nrf2 through PERK (Ho) which in endothelium includes Ho-1 binding to Nrf2 (Liu) and the 2) activation of CAMKII which may increase levels of cytokines and increase the likelihood of neuronal damage if not prevented. In cardiac cells, the inhibition of an isoform of CAMKII protects against intracellular levels of Ca+, H2O2 and acidosis in addition to protection from mitochondrial-induced apoptosis. Generally, H2O2 is generated through several mechanisms including from the mitochondrial respiratory chain and from activation of NADPH oxidases and can increase significantly during mitochondrial dysfunction. H2O2 signaling exerts prolonged signaling effects including those on dopamine release and down-regulation of CAMKII helps to prevent dopamine neurotoxicity(Cai, Bao). The activation of CAMKII from oxidative stress as noted by Xie, is responsible for "arrhythmia in diseased hearts and the heart's response to catecholamines in the "flight-fright" response (Cai). Also, CAMKII interacts with both TRPV1 and the NMDA receptor to alter their function. As for the latter, it may inhibit the downregulation of the NMDA receptor and increase the potential for pain generation and neurotoxicity.
Citations

Sickness Syndrome, CFS, Fibromyalgia, IL-10 and HO-1

A study that was published last year suggested that MCP-1/CCL2/CCr2 and eotaxin may be good biomarkers for fibromyalgia and identify a genetic component to the condition. (Zhang) Since then, researchers have noted that both chronic fatigue syndrome and fibromyalgia may be classified as inflammatory conditions when the exact cause of symptoms is not known. Interestingly, MCP-1 can cause inflammatory responses and therefore has the potential of contributing to sickness behavior syndrome which is a condition that results in behaviors often associated with people that are ill. Sickness behavior does not seem exclusive of human beings because similar behaviors have been observed in other animals. Maes concludes that oxidative and nitrosative stress contribute to the development of chronic fatigue which result in an increase inflammation, NF-kappaB, COX2, iNOS and damage to lipids and proteins. He further explains that triggers include strenuous exercise, LPS from gram negative bacteria, viruses and pshycological or physical stress. A few of the symtoms associated with sickness syndrome include fatigue, malaise, appetite changes, anxiety, depression, weight changes, sleep alterations and numerous others. (Maes) Previous studies show it can be stimulated by a variety of conditions including IGF-1, Tnf-a and Il-1b the latter two are produced as part of the stress response and modulated by the Nrf2 system that also stimulates induction of antioxidants. (Dantzer) Nrf2 has been shown to modulate metabolic homeostasis in adipocytes and is now linked with obesity. Nrf2 is responsible for detoxification of electrophiles and xenobiotics and the function of it can be altered by any number of environmental factors including but not limited to metals, nutrition, and other protein interactions such as the AhR which also may play a very important role in chemical sensitivity.

The severity of sickness syndrome has been demonstrated to be determined on the prevalence of the anti-inflammatory immune complex IL-10. When it is present the duration of sickness syndrome is less and the effects like memory and learning impairment are also decreased. (Richwine) Il-10 has been shown to reduce the levels of IFN-gamma and Tnf-a- induced production of superoxide and nadph oxidase 1 (NOX1) which would suggest prevention of ROS generation from it. (Kamizota) Il-10 also stimulates the induction of HO-1 and therefore may activate the Nrf2 pathway but HO-1 can act independantly. Inhibition of HO-1 significantly reduces the protective effects of Il-10 on Tnf-a by LPS. Lee et al shows that this relationship also involves carbon monoxide, a gasoneurotransmitter, on the protective effects of Il-10. Therefore this further suggests a possible involvement of Nrf2 considering that Nrf2 modulates the effects of carbon monoxide. (Lee) De Wilde demonstrated that production of Il-10 is completely abolished with inhibition of HO-1.

Nrf2 is now associated with protective effects in adipocytes. Eotaxin is a chemokine that is elevated in obesity because adipose tissue seems to be the predominant source of it. It is also an important inhibitor of MCP-1 and is a common factor in allergic reactions. Its presence at the site of allergic inflammation suggests coordinated cellular responses of allergic inflammation where both MCP-1 and eotaxin are present. (Olgilvie) Tnf-a is overexpressed in obesity (Uysal) and associated with insulin resistance and inhibition of the expression of numerous genes including PPAR-gamma and adiponectin. It is also an important inducer for prolonging the half-life of eotaxin.

Summary:

• Maes has suggested that a pathway to chronic fatigue syndrome is by LPS endotoxin and therefore because the production of Il-10 modulates the severity of sickness syndrome through HO-1. We can suggest that the alteration in signaling of Nrf2 could ultimately lead to CFS and sickness syndrome.
• Nrf2 is conserved in different organisms, the homolog in C elegans is skn-1. (An)
• Nrf2 can be ethnically derived and therefore some populations may be more susceptible to some of the triggers and have an increased risk for chronic fatigue syndrome. (Marzec, Dinos)
• EGCG has been shown to have positive effects on chronic fatigue syndrome in a mouse model of CFS. Studies have shown that EGCG increases induction of HO-1 through Nrf2.
  

All rights reserved.

Source Citations